An HLA-B27 polymorphism (B*2710) that is critical for T-cell recognition has limited effects on peptide specificity.
The B*2710 subtype differs from the HLA-B27 prototype (B*2705) only by having Glu instead of Val at position 152, in the alpha2 helix of the peptide-binding site. In spite of its structural similarity most alloreactive CTL raised against B*2705 fail to cross-react with B*2710. Indeed, of the residues that are polymorphic among HLA-B27 subtypes, the Val>Glu152 change has the greatest influence on HLA-B27 T-cell antigenicity. The molecular basis for this antigenic disparity was analyzed in this study. Sequence analysis indicated that B*2710-bound peptides have very similar motifs to B*2705-bound ones both at the main and auxiliary anchor positions. In addition, most of the individual ligands sequenced from B*2710 were previously found in B*2705. Together these results indicate that both subtypes have largely overlapping peptide repertoires. Molecular dynamics simulations of a common ligand in complex with either B*2710 or B*2705 failed to detect significant conformational changes in the peptidic main chain or in solvent accessibility of the side chains. In addition, modeling of the Val>Glu152 change into the MHC-peptide-TCR structure suggested a direct role of residue 152 in interaction with the TCR. Thus, the large differences in T-cell recognition between B*2710 and B*2705 are not explained by an effect of the Glu152 change on peptide specificity or conformation, but by different direct interactions with the TCR.
García
F
F
Centro de Biología Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autónoma de Madrid, Facultad de Ciencias, Cantoblanco, Spain.
Rognan
D
D
Lamas
J R
JR
Marina
A
A
López de Castro
J A
JA
D001665:Binding Sites; D002460:Cell Line; D015796:HLA-B27 Antigen / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D013601:T-Lymphocytes / Q000276:immunology*
D015796:HLA-B27 Antigen; D010455:Peptides